‘Eureka moment’

City of Hope researchers identify possible cause of type 1 diabetes

Ilene Schneider
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DUARTE, Calif.—About 1.5 million Americans suffer from type 1 diabetes (T1D), previously known as juvenile diabetes, which results from the loss of insulin-producing cells in the pancreas. While the root cause of T1D was believed to be the immune system mistakenly identifying those insulin-secreting beta cells as a potential danger and, in turn, destroying them, an international team of researchers has found a mechanism in which stressed beta cells are actually causing the immune response that leads to T1D.
City of Hope’s Dr. Bart Roep, the Chan Soon-Shiong Shapiro Distinguished Chair in Diabetes and professor/founding chair of the Department of Diabetes Immunology, along with researchers from the Leiden University Medical Center in the Netherlands, reported the results in the journal Nature Medicine. The work was supported by the Dutch Diabetes Research Foundation, the DON Foundation and the JDRF.
Roep said, “Ever since I started studying medicine, I was frustrated that we deal with the consequences, not the cause, of T1D. Now that we can identify the cause, we can address it with new types of therapies.”
Roep, who is director of The Wanek Family Project for Type 1 Diabetes, added, “Our findings show that type 1 diabetes results from a mistake of the beta cell, not a mistake of the immune system. The immune system does what it is supposed to do, which is respond to distressed or ‘unhappy’ tissue, as it would in infection or cancer. The mistake is in the beta cells, the most hardworking cells in the body.”
Roep said he had an epiphany about this three years ago—“one of those rare eureka moments in an area where one has to be prepared for disappointments.” He began to pursue it when he relocated to the City of Hope, an independent research and treatment center for cancer, diabetes and other life-threatening diseases. Not only is the City of Hope one of only 47 comprehensive cancer centers, the highest recognition bestowed by the National Cancer Institute, it is also a pioneer in the use of recombinant insulin, Roep noted.
In order to gain a better understanding of why the immune system attacks the body’s own source of insulin—the pancreatic beta cells in the islets of Langerhans—the team took some clues from cancer molecules that are targeted by the immune system after successful treatment of the cancer with immunotherapy. One such target is a so-called nonsense protein, which results from a misreading of a DNA sequence that makes a nonfunctional protein. Because the same type of protein error is also produced by the beta cells in T1D, Roep’s team believes that a “wrong read” of the insulin gene itself proves to be a major target of the immune system. This error product of the insulin gene is made when beta cells are stressed, Roep explained.
“Our study links antitumor immunity to islet autoimmunity, and may explain why some cancer patients develop type 1 diabetes after successful immunotherapy,” he added. “This is an incredible step forward in our commitment to cure this disease.”
As the paper, titled “Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes,” explains, the findings “further support the emerging concept that beta cells are destroyed in T1D by a mechanism comparable to classical antitumor responses where the immune system has been trained to survey dysfunctional cells in which errors have accumulated.”
“Now we can reread the RNA and create great antigens,” Roep said. He explained that the results of the study are giving him new insight for his work in developing new vaccines to desensitize the immune system so that it will tolerate islets again, as well as for research into combining immunotherapy with more traditional diabetes treatments to reinvigorate islets, adding, “We can take away the fuel of the immune response by making the beta cells happy, create new drugs that affect the beta cells and create new proteins.”
Roep described cancer and diabetes as “two sides of the same coin,” in which the body is producing too much or too little immune response. While immunotherapy is “a big breakthrough in cancer treatment,” some patients who are cured of cancer develop T1D, he said. “The window between cancer and diabetes could be the time to tweak the immune system and avoid the problem.”
“Some of the drugs that help with insulin production can help to relax the beta cells, even before the clinical manifestation of the disease,” he concluded.

Ilene Schneider

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